1. Field of the Invention
The present invention relates generally to the field of pharmaceutical chemistry. More particularly, it concerns the use of an effective amount of phenylacetic acid, phenylacetylglutamine, or phenylacetylisoglutamine, or pharmaceutically acceptable salts thereof, pharmaceutically acceptable precursors thereof, or pharmaceutically acceptable analogs thereof, singly or in any combination, and optionally including isoglutamine, in the treatment and prevention of hypercholesterolemia and hypertriglyceridemia.
2. Description of Related Art
In the United States, roughly 500,000 people die from coronary heart disease and 750,000 suffer heart attacks every year. Thousands more also die of stroke. A major cause of heart disease, heart attack, and stroke is atherosclerosis. Atherosclerosis is the growth of lesions on the walls of the aorta and other arteries, and its asymptomatic early stages are ubiquitous in populations with high-caloric, fat-rich diets such as are common in the United States and Europe. In its advanced stages, atherosclerotic lesions, commonly termed plaques, lead to constriction of the arterial lumen, resulting in impaired oxygen flow to the heart (angina) and the potential for thrombosis (blockage of blood flow by the presence of a clot), which may cause a heart attack or stroke.
Atherosclerotic lesions originate in the lining (intima) or middle layer (media) of the aorta and other arteries, as a focal overgrowth of smooth muscle cells. Recent investigations have uncovered evidence that a lesion may be a monoclonal overgrowth of smooth muscle cells. In other words, a lesion may correspond to a benign smooth muscle tumor. Although detailed understanding of this phenomenon remains the subject of inquiry, it has recently been postulated that smooth muscle cell proliferation may be caused, at least in part, by inactivation of the tumor suppressor gene p53.
Currently, factors that increase the risk of atherosclerosis are fairly well known. These factors include diets high in saturated fats and cholesterol, smoking, obesity, and conditions such as diabetes. Elimination or minimization of these risk factors has value in slowing the advancement of atherosclerosis. Of these, minimizing cholesterol intake, especially LDL cholesterol, has been highly publicized in recent years. It has been reported that both native and oxidized LDL cholesterol stimulate DNA synthesis in cultured human smooth muscle cells (Stiko-Rahm et al., Arterioscler. Thromb. 12, 9: 1099–1109 (1992)).
Several observations complicate the minimization of cholesterol intake. One is patient compliance with dietary restrictions. A regimen of pharmaceutical treatment to lower cholesterol levels may be more readily complied with than would a change in lifelong eating habits. Another observation is that hypercholesterolemia can occur due to non-dietary conditions, for example, essential hypercholesterolemia, a familial trait characterized by a genetically-determined low level of LDL receptors, and liver disorders which impair excretion of cholesterol in the bile, for example, jaundice. These patients would benefit from a pharmaceutical treatment to lower cholesterol levels.
Triglycerides are the form in which fat is stored by the body. High triglyceride levels have been observed in patients with hypercholesterolemia and other risk factors for heart disease. Although it is not known if hypertriglyceridemia leads to heart disease, a pharmaceutical treatment to lower triglyceride levels would be of benefit to patients.
It has been known for some time that compounds such as 3-phenylacetylamino-2,6-piperidinedione and its hydrolysis products, such as phenylacetic acid, and salts, precursors, and analogs thereof (together, “3-phenylacetylamino-2,6-piperidinedione and its derivatives”), can block the formation of iso-pentenylpyrophosphate from 5-pyrophosphomevalonate, a reaction in the pathway of cholesterol biosynthesis; as a result, these compounds may lower serum cholesterol levels. Therefore, it was desirable to determine which, if any, of ˜3-phenylacetylamino-2,6-piperidinedione and its derivatives can lower serum cholesterol levels, and thus can form the basis of a pharmaceutical composition useful in treating or preventing hypercholesterolemia. Derivatives of 3-phenylacetylamino-2,6-piperidinedione that exhibit such activity are disclosed herein.